title: Physiological activation of cholinergic inputs controls associative synaptic plasticity via modulation of endocannabinoid signaling.
abstract: Cholinergic neuromodulation controls long-term synaptic plasticity underlying memory, learning, and adaptive sensory processing. However, the mechanistic interaction of cholinergic, neuromodulatory inputs with signaling pathways underlying long-term potentiation (LTP) and long-term depression (LTD) remains poorly understood. Here, we show that physiological activation of muscarinic acetylcholine receptors (mAChRs) controls the size and sign of associative long-term synaptic plasticity via interaction with endocannabinoid signaling. Our findings indicate that synaptic or pharmacological activation of postsynaptic M1/M3 converts postsynaptic Hebbian LTP to presynaptic anti-Hebbian LTD in principal neurons of the dorsal cochlear nucleus (DCN). This conversion is also dependent on NMDA receptor (NMDAR) activation and rises in postsynaptic Ca(2+). While NMDAR activation and Ca(2+) elevation lead to LTP, when these events are coordinated with simultaneous activation of M1/M3 mAChRs, anti-Hebbian LTD is induced. Anti-Hebbian LTD is mediated by a postsynaptic G-protein-coupled receptor intracellular signaling cascade that activates phospholipase C and that leads to enhanced endocannabinoid signaling. Moreover, the interaction between postsynaptic M1/M3 mAChRs and endocannabinoid signaling is input specific, as it occurs only in the parallel fiber inputs, but not in the auditory nerve inputs innervating the same DCN principal neurons. Based on the extensive distribution of cholinergic and endocannabinoid signaling, we suggest that their interaction may provide a general mechanism for dynamic, context-dependent modulation of associative synaptic plasticity.
authors.affiliation: Departments of Otolaryngology and Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Thanos
authors.initials: T
authors.lastname: Tzounopoulos
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002799:Cholinergic Fibers / Q000378:metabolism / Q000502:physiology*; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009473:Neuronal Plasticity / Q000502:physiology*; D011930:Reaction Time / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D011976:Receptors, Muscarinic